In principal, details on the molecular orientation of hemoglobin S units in the various positions of the fibers could be deduced from electron microscopy at approximately 20 A resolution by making use of the asymmetry of the molecule and various clefts between subunits that would be defined at this resolution. Our work to date has achieved a resolution by new approaches to fiber preparation and image processing. Other goals include experiments aimed at trapping molecular species at early stages of assembly (using cross-linking reagents) in order to determine the structural pathway of fiber assembly and examination of fibers formed from hybrid molecules composed of beta chains from hemoglobin S and alpha chains from various mutant hemoglobins. These latter studies should aid in the identification of the portions of the hemoglobin molecules at various intermolecular contacts. Accumulation of additional information of this type should enable us to evaluate the validity of our proposed molecular model for the fibers or ascertain what modifications are required.